Top

Current Atherosclerosis Reports

Published in:

01-05-2017 | Coronary Heart Disease (S. Virani and S. Naderi, Section Editors)

Radiation-Induced Cardiovascular Disease

Authors: Deepa Raghunathan, Misha Iftikhar Khilji, Saamir A. Hassan, Syed Wamique Yusuf

Published in: Current Atherosclerosis Reports | Issue 5/2017

Abstract

Purpose of review

Thoracic radiation therapy is an effective treatment for several malignancies, such as Hodgkin’s lymphoma and breast cancer. Over the years, however, the incidence of cardiovascular events has increased in these patients, notably in younger survivors who do not have traditional risk factors. This review summarizes the pathology, incidence, clinical presentation, and management of cardiac events after radiation therapy.

Recent findings

Mediastinal radiation therapy accelerates the atherosclerosis process, resulting in early onset coronary artery disease. Valvular disease due to radiation therapy typically affects the left-sided valves, with aortic regurgitation being the most common. Rarely, it may lead to aortic stenosis requiring surgical interventions. Pericardial involvement includes acute and chronic pericardial disease and pericardial effusion. New studies are investigating the prevalence and pathogenesis of autonomic dysfunction in cancer survivors who have undergone mediastinal and neck radiation.

Summary

Radiation therapy itself causes vascular endothelial dysfunction, resulting in clinical cardiovascular events, manifesting many years after completion of therapy. There remains little guidance regarding screening and therapies to prevent cardiovascular events in this population.

Boivin JF, Hutchison GB, Lubin JH, Mauch P. Coronary artery disease mortality in patients treated for Hodgkin’s disease. Cancer. 1992;69(5):1241–7.CrossRefPubMed

• Fidler MM, Reulen RC, Henson KE, Kelly J, Cutter D, Levitt GA, et al. Population-based long-term cardiac-specific mortality among 34,489 five-year survivors of childhood cancer in Great Britain. Circulation. 2017. doi:10.1161/CIRCULATIONAHA.116.024811. This prospective study followed patients treated for cancer in childhood. Those treated in the 1980s had a higher incidence of cardiac mortality and morbidity compared to those treated after the 1990s, suggesting that changes in the treatment process has lowered but not elimiated cardiac risk.PubMedPubMedCentral

McGale P, Darby SC, Hall P, Adolfsson J, Bengtsson NO, Bennet AM, et al. Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Radiother Oncol. 2011;100(2):167–75. doi:10.1016/j.radonc.2011.06.016.CrossRefPubMed

• Le Gallic C, Phalente Y, Manens L, Dublineau I, Benderitter M, Gueguen Y, et al. Chronic internal exposure to low dose 137Cs induces positive impact on the stability of atherosclerotic plaques by reducing inflammation in ApoE−/−mice. PLoS One. 2015;10(6):e0128539. doi:10.1371/journal.pone.0128539. This study characterized atherosclerotic lesions in mice exposed to low dose radiation.CrossRefPubMedPubMedCentral

• Linton MF, Babaev VR, Huang J, Linton EF, Tao H, Yancey PG. Macrophage apoptosis and efferocytosis in the pathogenesis of atherosclerosis. Circ J. 2016;80(11):2259–68. doi:10.1253/circj.CJ-16-0924. This review summarized the effects of macrophages on the development of atherosclerosis.CrossRefPubMed

Shimizu Y, Kodama K, Nishi N, Kasagi F, Suyama A, Soda M, et al. Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950–2003. BMJ. 2010;340:b5349. doi:10.1136/bmj.b5349.CrossRefPubMedPubMedCentral

Ng AK, Bernardo MP, Weller E, Backstrand KH, Silver B, Marcus KC, et al. Long-term survival and competing causes of death in patients with early-stage Hodgkin’s disease treated at age 50 or younger. J Clin Oncol. 2002;20(8):2101–8. doi:10.1200/JCO.2002.08.021.CrossRefPubMed

Swerdlow AJ, Higgins CD, Smith P, Cunningham D, Hancock BW, Horwich A, et al. Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst. 2007;99(3):206–14. doi:10.1093/jnci/djk029.CrossRefPubMed

Van Der Meeren A, Squiban C, Gourmelon P, Lafont H, Gaugler MH. Differential regulation by IL-4 and IL-10 of radiation-induced IL-6 and IL-8 production and ICAM-1 expression by human endothelial cells. Cytokine. 1999;11(11):831–8. doi:10.1006/cyto.1999.0497.CrossRef

10.

Bhattacharya S, Asaithamby A. Ionizing radiation and heart risks. Semin Cell Dev Biol. 2016;58:14–25. doi:10.1016/j.semcdb.2016.01.045.CrossRefPubMed

11.

• Wang Y, Boerma M, Zhou D. Ionizing radiation-induced endothelial cell senescence and cardiovascular diseases. Radiat Res. 2016;186(2):153–61. doi:10.1667/RR14445.1. This study suggested a mechanism for radiation-induced endothelial dysfunction.CrossRefPubMedPubMedCentral

12.

Korpela E, Liu SK. Endothelial perturbations and therapeutic strategies in normal tissue radiation damage. Radiat Oncol. 2014;9:266. doi:10.1186/s13014-014-0266-7.CrossRefPubMedPubMedCentral

13.•

Taunk NK, Haffty BG, Kostis JB, Goyal S. Radiation-induced heart disease: pathologic abnormalities and putative mechanisms. Front Oncol. 2015;5:39. doi:10.3389/fonc.2015.00039. A review postulating the pathology of heart disease in radiation-exposed patients.CrossRefPubMedPubMedCentral

14.

• Mulrooney DA, Armstrong GT, Huang S, Ness KK, Ehrhardt MJ, Joshi VM, et al. Cardiac outcomes in adult survivors of childhood cancer exposed to cardiotoxic therapy: a cross-sectional study. Ann Intern Med. 2016;164(2):93–101. doi:10.7326/M15-0424. A prospective study that showed the incidence of heart disease in patients treated with cardiotoxic radiation and chemotherapy in childhood.CrossRefPubMedPubMedCentral

15.

• Boero IJ, Paravati AJ, Triplett DP, Hwang L, Matsuno RK, Gillespie EF, et al. Modern radiation therapy and cardiac outcomes in breast cancer. Int J Radiat Oncol Biol Phys. 2016;94(4):700–8. doi:10.1016/j.ijrobp.2015.12.018. A retrospective study that reviewed the incidence of cardiovascular disease requiring interventions in women treated with radiation for breast cancer.CrossRefPubMed

16.

Preston DL, Shimizu Y, Pierce DA, Suyama A, Mabuchi K. Studies of mortality of atomic bomb survivors. Report 13: solid cancer and noncancer disease mortality: 1950–1997. Radiat Res. 2003;160(4):381–407.CrossRefPubMed

17.

Yusuf SW, Sami S, Daher IN. Radiation-induced heart disease: a clinical update. Cardiol Res Pract. 2011;2011:317659. doi:10.4061/2011/317659.PubMedPubMedCentral

18.

Tungjai M, Whorton EB, Rithidech KN. Persistence of apoptosis and inflammatory responses in the heart and bone marrow of mice following whole-body exposure to 28Silicon (28Si) ions. Radiat Environ Biophys. 2013;52(3):339–50. doi:10.1007/s00411-013-0479-4.CrossRefPubMed

19.

Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987–98. doi:10.1056/NEJMoa1209825.CrossRefPubMed

20.

Heidenreich PA, Schnittger I, Strauss HW, Vagelos RH, Lee BK, Mariscal CS, et al. Screening for coronary artery disease after mediastinal irradiation for Hodgkin’s disease. J Clin Oncol. 2007;25(1):43–9. doi:10.1200/JCO.2006.07.0805.CrossRefPubMed

21.

Orzan F, Brusca A, Conte MR, Presbitero P, Figliomeni MC. Severe coronary artery disease after radiation therapy of the chest and mediastinum: clinical presentation and treatment. Br Heart J. 1993;69(6):496–500.CrossRefPubMedPubMedCentral

22.

Marks LB, Yu X, Prosnitz RG, Zhou SM, Hardenbergh PH, Blazing M, et al. The incidence and functional consequences of RT-associated cardiac perfusion defects. Int J Radiat Oncol Biol Phys. 2005;63(1):214–23. doi:10.1016/j.ijrobp.2005.01.029.CrossRefPubMed

23.

Gayed IW, Liu HH, Yusuf SW, Komaki R, Wei X, Wang X, et al. The prevalence of myocardial ischemia after concurrent chemoradiation therapy as detected by gated myocardial perfusion imaging in patients with esophageal cancer. J Nucl Med. 2006;47(11):1756–62.PubMed

24.

• Caro-Codon J, Jimenez-Valero S, Galeote G, Sanchez-Recalde A, Moreno R. Radiation-induced coronary artery disease: useful insights from OCT. Int J Cardiol. 2016;202:535–6. doi:10.1016/j.ijcard.2015.09.095. A case study that showed the morphology of coronary vessels affected by radiation therapy using optical coherence tomography.CrossRefPubMed

25.

Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, van Putten WL, Levendag PC. Ischemic heart disease after mantlefield irradiation for Hodgkin’s disease in long-term follow-up. Radiother Oncol. 1999;51(1):35–42.CrossRefPubMed

26.

Brosius 3rd FC, Waller BF, Roberts WC. Radiation heart disease: analysis of 16 young (aged 15 to 33 years) necropsy patients who received over 3,500 rads to the heart. Am J Med. 1981;70(3):519–30.CrossRefPubMed

27.

Brown ML, Schaff HV, Sundt TM. Conduit choice for coronary artery bypass grafting after mediastinal radiation. J Thorac Cardiovasc Surg. 2008;136(5):1167–71. doi:10.1016/j.jtcvs.2008.07.005.CrossRefPubMed

28.

• Skytta T, Tuohinen S, Boman E, Virtanen V, Raatikainen P, Kellokumpu-Lehtinen PL. Troponin T-release associates with cardiac radiation doses during adjuvant left-sided breast cancer radiotherapy. Radiat Oncol. 2015;10:141. doi:10.1186/s13014-015-0436-2. This study showed that during radiation, troponin-T levels were elevated, though it is still unclear whether this increase correlates with cardiovascular damage.CrossRefPubMedPubMedCentral

29.

•Gomez DR, Yusuf SW, Munsell MF, Welsh JW, Liao Z, Lin SH, et al. Prospective exploratory analysis of cardiac biomarkers and electrocardiogram abnormalities in patients receiving thoracic radiation therapy with high-dose heart exposure. J Thorac Oncol. 2014;9(10):1554–60. doi:10.1097/JTO.0000000000000306. This study demonstrated elevated brain natriuretic peptide, troponin-I, and electrocardiogram changes after radiation therapy. Further investigation is warranted to determine whether these biomarkers could be used to screen for cardiovascular risks in cancer survivors treated with radiation.CrossRefPubMedPubMedCentral

30.

Kozak KR, Hong TS, Sluss PM, Lewandrowski EL, Aleryani SL, Macdonald SM, et al. Cardiac blood biomarkers in patients receiving thoracic (chemo) radiation. Lung Cancer. 2008;62(3):351–5. doi:10.1016/j.lungcan.2008.03.024.CrossRefPubMed

31.

• Bijl JM, Roos MM, van Leeuwen-Segarceanu EM, Vos JM, Bos WJ, Biesma DH, et al. Assessment of valvular disorders in survivors of Hodgkin’s lymphoma treated by mediastinal radiotherapy ± chemotherapy. Am J Cardiol. 2016;117(4):691–6. doi:10.1016/j.amjcard.2015.11.027. This study found that asymptomatic aortic regurgitation is the most common valvular disease and was more prevalent the more years after radiation exposure.CrossRefPubMed

32.•

Cutter DJ, Schaapveld M, Darby SC, Hauptmann M, van Nimwegen FA, Krol AD et al. Risk of valvular heart disease after treatment for Hodgkin lymphoma. J Natl Cancer Inst. 2015;107(4). doi:10.1093/jnci/djv008. This retrospective study reviewed the incidence of valvular heart disease in patients treated with radiation therapy for Hodgkin lymphoma.

33.

Veinot JP, Edwards WD. Pathology of radiation-induced heart disease: a surgical and autopsy study of 27 cases. Hum Pathol. 1996;27(8):766–73.CrossRefPubMed

34.

• Groarke JD, Nguyen PL, Nohria A, Ferrari R, Cheng S, Moslehi J. Cardiovascular complications of radiation therapy for thoracic malignancies: the role for non-invasive imaging for detection of cardiovascular disease. Eur Heart J. 2014;35(10):612–23. doi:10.1093/eurheartj/eht114. This review article suggested the use of non-invasive cardiac imaging to screen patients treated with radiation therapy for cardiovascular complications.CrossRefPubMed

35.

Heidenreich PA, Hancock SL, Lee BK, Mariscal CS, Schnittger I. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol. 2003;42(4):743–9.CrossRefPubMed

36.

• Cuomo JR, Sharma GK, Conger PD, Weintraub NL. Novel concepts in radiation-induced cardiovascular disease. World J Cardiol. 2016;8(9):504–19. doi:10.4330/wjc.v8.i9.504. This review summarizes the effects of radiation therapy on the heart in cancer survivors.CrossRefPubMedPubMedCentral

37.

• Ogino I, Watanabe S, Iwahashi N, Kosuge M, Sakamaki K, Kunisaki C, et al. Symptomatic radiation-induced cardiac disease in long-term survivors of esophageal cancer. Strahlenther Onkol. 2016;192(6):359–67. doi:10.1007/s00066-016-0956-1. This study found that efforts to reduce radiation exposure to the heart reduced the incidence of cardiovascular complications later in life.CrossRefPubMed

38.

Yusuf SW, Sarfaraz A, Durand JB, Swafford J, Daher IN. Management and outcomes of severe aortic stenosis in cancer patients. Am Heart J. 2011;161(6):1125–32. doi:10.1016/j.ahj.2011.03.013.CrossRefPubMed

39.

• Moreira LA, Silva EN, Ribeiro ML, Martins Wde A. Cardiovascular effects of radiotherapy on the patient with cancer. Rev Assoc Med Bras (1992). 2016;62(2):192–6. doi:10.1590/1806-9282.62.02.192. This literature review of patients treated with radiation therapy and the incidence, possible pathology, clinical symptoms and management of cardiovascular disease.CrossRef

40.

Carmel RJ, Kaplan HS. Mantle irradiation in Hodgkin’s disease. An analysis of technique, tumor eradication, and complications. Cancer. 1976;37(6):2813–25.CrossRefPubMed

41.

Mousavi N, Nohria A. Radiation-induced cardiovascular disease. Curr Treat Options Cardiovasc Med. 2013;15(5):507–17. doi:10.1007/s11936-013-0259-0.CrossRefPubMed

42.

• Nathan PC, Amir E, Abdel-Qadir H. Cardiac outcomes in survivors of pediatric and adult cancers. Can J Cardiol. 2016;32(7):871–80. doi:10.1016/j.cjca.2016.02.065. The study reviewed the incidence of cardiovascular disease in both children and adult cancer patients.CrossRefPubMed

43.

Kucharska W, Negrusz-Kawecka M, Gromkowska M. Cardiotoxicity of oncological treatment in children. Adv Clin Exp Med. 2012;21(3):281–8.PubMed

44.

• Beukema JC, van Luijk P, Widder J, Langendijk JA, Muijs CT. Is cardiac toxicity a relevant issue in the radiation treatment of esophageal cancer? Radiother Oncol. 2015;114(1):85–90. doi:10.1016/j.radonc.2014.11.037. This study looked at patients treated with radiation therapy for esophageal cancer and looked at the incidence of cardiac disease.CrossRefPubMed

45.

Ling LH, Oh JK, Schaff HV, Danielson GK, Mahoney DW, Seward JB, et al. Constrictive pericarditis in the modern era: evolving clinical spectrum and impact on outcome after pericardiectomy. Circulation. 1999;100(13):1380–6.CrossRefPubMed

46.

Bertog SC, Thambidorai SK, Parakh K, Schoenhagen P, Ozduran V, Houghtaling PL, et al. Constrictive pericarditis: etiology and cause-specific survival after pericardiectomy. J Am Coll Cardiol. 2004;43(8):1445–52. doi:10.1016/j.jacc.2003.11.048.CrossRefPubMed

47.

Morton DL, Glancy DL, Joseph WL, Adkins PC. Management of patients with radiation-induced pericarditis with effusion: a note on the development of aortic regurgitation in two of them. Chest. 1973;64(3):291–7.CrossRefPubMed

48.

Guldner L, Haddy N, Pein F, Diallo I, Shamsaldin A, Dahan M, et al. Radiation dose and long term risk of cardiac pathology following radiotherapy and anthracyclin for a childhood cancer. Radiother Oncol. 2006;81(1):47–56. doi:10.1016/j.radonc.2006.08.020.CrossRefPubMed

49.

Mezzaroma E, Di X, Graves P, Toldo S, Van Tassell BW, Kannan H, et al. A mouse model of radiation-induced cardiomyopathy. Int J Cardiol. 2012;156(2):231–3. doi:10.1016/j.ijcard.2012.01.038.CrossRefPubMedPubMedCentral

50.

Chello M, Mastroroberto P, Romano R, Zofrea S, Bevacqua I, Marchese AR. Changes in the proportion of types I and III collagen in the left ventricular wall of patients with post-irradiative pericarditis. Cardiovasc Surg. 1996;4(2):222–6.CrossRefPubMed

51.

• Al-Kindi SG, Oliveira GH. Heart transplantation outcomes in radiation-induced restrictive cardiomyopathy. J Card Fail. 2016;22(6):475–8. doi:10.1016/j.cardfail.2016.03.014. This study followed cancer survivors who had history of chest radiation therapy and their five year survival rate post heart transplantation.CrossRefPubMed

52.•

Marmagkiolis K, Finch W, Tsitlakidou D, Josephs T, Iliescu C, Best JF, et al. Radiation toxicity to the cardiovascular system. Curr Oncol Rep. 2016;18(3):15. doi:10.1007/s11912-016-0502-4. This review summarized the cardiovascular effects of radiation therapy on cancer survivors.CrossRefPubMed

53.

Totterman KJ, Pesonen E, Siltanen P. Radiation-related chronic heart disease. Chest. 1983;83(6):875–8.CrossRefPubMed

54.

Orzan F, Brusca A, Gaita F, Giustetto C, Figliomeni MC, Libero L. Associated cardiac lesions in patients with radiation-induced complete heart block. Int J Cardiol. 1993;39(2):151–6.CrossRefPubMed

55.

Adams MJ, Lipshultz SE, Schwartz C, Fajardo LF, Coen V, Constine LS. Radiation-associated cardiovascular disease: manifestations and management. Semin Radiat Oncol. 2003;13(3):346–56. doi:10.1016/S1053-4296(03)00026-2.CrossRefPubMed

56.

Rosenwinkel ET, Bloomfield DM, Arwady MA, Goldsmith RL. Exercise and autonomic function in health and cardiovascular disease. Cardiol Clin. 2001;19(3):369–87.CrossRefPubMed

57.

• Groarke JD, Tanguturi VK, Hainer J, Klein J, Moslehi JJ, Ng A, et al. Abnormal exercise response in long-term survivors of hodgkin lymphoma treated with thoracic irradiation: evidence of cardiac autonomic dysfunction and impact on outcomes. J Am Coll Cardiol. 2015;65(6):573–83. doi:10.1016/j.jacc.2014.11.035. This study demonstrated that autonomic dysfunction could be a late side effect of radiation therapy.CrossRefPubMed

58.

Hoca A, Yildiz M, Ozyigit G. Evaluation of the effects of mediastinal radiation therapy on autonomic nervous system. Med Oncol. 2012;29(5):3581–6. doi:10.1007/s12032-012-0237-5.CrossRefPubMed

59.

Aung T, Fan W, Krishnamurthy M. Recurrent syncope, orthostatic hypotension and volatile hypertension: think outside the box. J Community Hosp Intern Med Perspect. 2013;3(2). doi:10.3402/jchimp.v3i2.20741.

60.

Huang CC, Huang TL, Hsu HC, Chen HC, Lin HC, Chien CY, et al. Long-term effects of neck irradiation on cardiovascular autonomic function: a study in nasopharyngeal carcinoma patients after radiotherapy. Muscle Nerve. 2013;47(3):344–50. doi:10.1002/mus.23530.CrossRefPubMed

61.

Sharabi Y, Dendi R, Holmes C, Goldstein DS. Baroreflex failure as a late sequela of neck irradiation. Hypertension. 2003;42(1):110–6. doi:10.1161/01.HYP.0000077441.45309.08.CrossRefPubMed

62.

Mulrooney DA, Yeazel MW, Kawashima T, Mertens AC, Mitby P, Stovall M, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009;339:b4606. doi:10.1136/bmj.b4606.CrossRefPubMedPubMedCentral

63.

van der Pal HJ, van Dalen EC, van Delden E, van Dijk IW, Kok WE, Geskus RB, et al. High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol. 2012;30(13):1429–37. doi:10.1200/JCO.2010.33.4730.CrossRefPubMed

64.

• Daniels LA, Krol AD, de Graaf MA, Scholte AJ, Van’t Veer MB, Putter H, et al. Screening for coronary artery disease after mediastinal irradiation in Hodgkin lymphoma survivors: phase II study of indication and acceptancedagger. Ann Oncol. 2014;25(6):1198–203. doi:10.1093/annonc/mdu130. This study looked at computed tomography coronary angiography as a possible screening tool for radiation induced coronary artery disease.CrossRefPubMed

Title: Radiation-Induced Cardiovascular Disease
Authors: Deepa Raghunathan
Misha Iftikhar Khilji
Saamir A. Hassan
Syed Wamique Yusuf
Publication date: 01-05-2017
Publisher: Springer US
Published in: Current Atherosclerosis Reports / Issue 5/2017
Print ISSN: 1523-3804
Electronic ISSN: 1534-6242
DOI: https://doi.org/10.1007/s11883-017-0658-x

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose of review

Recent findings

Summary

Please log in to get access to this content

Other articles of this Issue 5/2017

The Role for Cardiovascular Remodeling in Cardiovascular Outcomes

Coronary Heart Disease in the Middle East and North Africa: Current Status and Future Goals

HIV Infection and Risk of Cardiovascular Diseases Beyond Coronary Artery Disease

Erratum to: The Role of Adipocytokines in Coronary Atherosclerosis

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials